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Case Reports
.2012 Jan;158A(1):182-7.
doi: 10.1002/ajmg.a.34355. Epub 2011 Nov 21.

Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome

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Case Reports

Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome

Jane Gillis et al. Am J Med Genet A.2012 Jan.

Abstract

Timothy syndrome (TS) is an autosomal dominant condition with the constellation of features including prolonged QT interval, hand and foot abnormalities, and mental retardation or autism. Splawski et al. [2004] previously described two phenotypes associated with TS distinguished by two unique and different mutations within the CACNA1C gene. We report on a newborn who presented with prolonged QT interval and associated polymorphic ventricular tachycardia, dysmorphic facial features, syndactyly of the hands and feet, and joint contractures, suggestive of TS. He developed a stroke, subsequent intractable seizures, and was found to have cortical blindness and later profound developmental delay. Initial targeted mutation analysis did not identify either of the previously described TS associated mutations; however, full gene sequencing detected a novel CACNA1C gene mutation (p.Ala1473Gly). The clinical and genetic findings in our case expand both the clinical and molecular knowledge of TS.

Copyright © 2011 Wiley Periodicals, Inc.

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Figures

Figure 1
Figure 1
a: Photographs of our patient at 3 months of age showing dysmorphic facial features, sloped shoulders and joint limitation. To the right note the syndactyly and contractures of hands and feet bilaterally (LH – left hand; RH – right hand; LF – left foot; RF – right foot)b: Photographs of our patient at 4 years of age showing myopathic facies, downslanting palpebral fissures, and same hand and foot anomalies as previous.
Figure 2
Figure 2
Standard 12-lead ECG recorded at 2 days of age showing rightward QRS axis deviation, incomplete right bundle branch block, and striking QT interval prolongation with a raw measurement of 464ms rate-corrected to 640ms using Bazett’s formula. There is a subtle T-wave alternans most apparent in leads I and II.
Figure 3
Figure 3
Patient’s CT scan and MRA: (a) CNS and craniofacial montage: CT 3D reconstruction at 4 days of age reveals markedly enlarged sutures and anterior fontanel for gestational age. (b) MRA at 9 days of age demonstrates incidental dominant right anterior cerebral artery and bilaterally patent middle cerebral arteries. (c) Axial T2W image and DWI (d) at 9 days of age reveal subacute left hemispheric stroke with persistence of diffusion restriction (arrow).
Figure 4
Figure 4
Radiographs of the hands (a,b) demonstrate bilateral ulnar deviation, adduction of the thumbs and unilateral soft tissue syndactyly of digits 4 and 5 (arrow). Pelvic AP radiograph (c) reveals shallow steep acetabuli and femoral head dislocation. Lateral foot radiograph (d) demonstrates vertical talus and pes planus deformity.
Figure 5
Figure 5
Sequencing of theCACNA1C gene identified a novel mutation c.4418C>G in exon 36, predicting an amino acid substitution of a glycine for an alanine at codon 1473 (p.Ala1473Gly). The same analysis done on both parents did not identify the mutation in either of them.
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References

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